Process for preparing trisubstituted methyl chloroformates



United States Patent "cc 3,152,167 PROCESS FOR PREPARlNG TRISUBSTITUTEDMETHYL CHLGROFUfiVIATES Meyer Sletzinger, North Plainfield, N.J.,assignor to Merck & Co., Inc., Railway, N.J., a corporation of NewJersey No Drawing. Filed May 31, 1969, Ser. No. 32,562 9 Claims. (Cl.269-463) This invention relates to compounds having muscle relaxing andtranquilizing action, and provides novel procedures useful in theirpreparation.

The active muscle relaxing and tranquilizing compounds are of thefollowing structural formula:

wherein R is an alkyl or alkyne substituent, R is an alkyl group, and Ris an alkyl group, with the provisos that R and R have a total of 3 to 4carbon atoms and R has 1 to 2 carbon atoms.

Of particular interest as the muscle relaxing and tranquilizingcompounds are the compounds described and claimed in copendingapplication Serial No. 774,091, filed November 17, 1958, and now US.Patent 2,972,564. The compounds of the said copending application are ofthe above structural formula except the the Rs are of more limitedmeaning, R and R being alkyl substituents having a combined total of 4carbon atoms, and R being an alkyl substituent having 1 to 2 carbonatoms.

Specific compounds embraced by Formula I are the following:

3-methyl-3-pentanol carbamate, 3-ethyl-3-pentanol carbamate,Z-methyl-Z-pentanol carbamate, 3-methyl-3-ol-pentyne-l carbamate, and3-methyl-3-ol-butyne-l carbamate.

The following structural formulae for two of these compounds willfacilitate understanding of the nomenclature employed.

zHa CH3 C2 5 OfiNHs (H) 3-methyl-3-pentano1 carbamate HCEC CH3 C2 HsONE:

(H) (III) 3-methy1-3-o1-pentyne-1 earbamate Compounds of Formula I aboveposesss muscle relaxing properties and selective tranquilizing effectson the central nervous system. They are effective as skeletal relaxants,and are useful in the management of anxiety and tension states with aminimal incidence of undesirable side elfects. These properties appearto be unique with the foregoing compounds, and are not found in evenquite closely related carbamate compounds.

The compounds are active when adminstered orally, rectally orparenterally. They are only slightly soluble in Water, however, and fortherapeutic use, in order to ensure proper absorption and favorabletherapeutic effect, they are preferably incorporated in suitablepharmaceutical carriers. In clinical use of these compounds therecommended dosage is 50 to 800 mgs., preferably 100 iidgilhl PatentedGet. 6, 1954 to 400 mg, of active drug 2 to 4 times per day. Thus inpreparing tablets, capsules, elixirs, suppositories or other dosageforms with pharmaceutical carriers the formulation should preferablycontain to 409 mg. of active drug per dosage unit.

A principal object of this invention is to provide the foregoingcompounds in a commercially feasible and tech nically simple manner insuch yields and purity as materially to lower their cost of production.Other objects will become apparent from the following description.

According to the invention, the muscle relaxing and tranquilizingcompounds are made as follows: An alcohol of the formula,

wherein R is an alkyl or alkyne substituent, R is an alkyl group, and Ris an alkyl group, with the provisos that R and R have a total of 3 to4- carbon atoms and R has 1 to 2 carbon atoms, is placed in contact withan alkali metal, alkali metal hydride or alkali metal amide, in thepresence of an inert organic solvent. The reaction is continued at atemperature and for a time suflicient for formation of the correspondingalkali metal alcoholate as a solute in the inert organic solvent. Theresulting alkali metal alcoholate solution is added to a solution ofphosgene in an organic solvent to provide a reaction mixture of thesolutions and the reaction mixture is maintained at a temperature andfor a time suitable for formation of the corresponding chloroformate ofthe alcohol, i.e., a chloroformate of the formula,

R1 R3 C R2 0001 wherein the Rs have the same meaning as above noted.Finally, the chloroformate is reacted with ammonia, to provide acompound according to Formula 1, above.

The step of forming the alcoholate solution is novel, as is also thestep of reacting the alcoholate solution with the phosgene solution.

A feature of the invention is the utilization of a solution of thesodium alcoholate in the alcoholate-phosgene reaction. This procedure isof course dependent on the alkali metal alcoholate being soluble in theinert organic solvent. The solubility of the alcoholate in such solventsis surprising and is a novel discovery.

Since the alcoholate is provided as a solute in an inert organicsolvent, it is possible to add the alcoholate to the phosgene, and thismanner of contacting the reactants is significant. If the phosgene wereadded to the alcoholate, which would be necessary if the alcoholate wereinsoluble, side reactions substantially reducing the yield would occur.

In a preferred embodiment of the invention, in the reaction mixtureobtained by adding the alcoholate solution to the phosgene solution,there is included an ether in an amount effective to provide improvedyield of the chloroformate.

Going now to a more detailed discussion of the procedure according tothe invention, among the reactants which can be employed in theformation of the alkali metal alcoholate are sodium metal, potassiummetal, sodium amide, potassium amide, sodium hydride and potassiumhydride. Other corresponding alkali metal and compounds can be used, ifdesired. The preferred material is alkali metal, particularly sodium.

A noted above, the alkali metal alcoholate is formed in the presence ofan inert solvent. Suitable solvents are 3 organic solvents, for example,benzene, toluene, xylene, hexane, cyclohexane, and petroleum ether. Ingeneral, hydrocarbon solvents boiling at about 80 C. or above aresuitable. The preferred solvent is toluene since it is a good solventfor the alcoholate and has a boiling point well suited for the processof the invention.

The amounts of the alkali metal material and alcohol used are preferablystoichiometric amounts, since the use of such amounts is more economicaland provides an improved product in terms of purity. The amount of inertsolvent should be an amount suflicient to dissolve the alcoholateproduced. There is no upper limit. About 25 ml. of solvent per 50 gramsof alcohol can be used, and preferably the amount of solvent is 40-60ml. per 50 grams of alcohol. The temperature for the reaction can be 80C. up to the boiling point of the solvent and the preferred temperatureis the reflux temperature. Thus, if xylene is the solvent, the refluxtemperature will be about 139 C. Atmospheric pressure is suitable. Thetime for the reaction should be until the reaction is complete, and thisi indicated by the solution of all the alkali material. Up to about 18hours for the reaction is reasonable but longer periods areuneconomical.

Preferred conditions for the alcoholate forming reaction are the use oftoluene as the inert solvent, the use of sodium as the alkali material,and running the reaction at the reflux temperature of about 118 C. Underthese conditions good time-yield results are obtained.

For the reaction of the alcoholate and phosgene, the alcoholatedissolved in an inert solvent as described above for preparation of thealcoholate, and phosgene contained in an organic solvent, are admixed.The inert organic solvent in which the phosgene is dissolved can beselected from among those described above as suitable for preparation ofthe alcoholate. esirably, an ether is included in the reaction mixtureof the alcoholate solution and phosgene solution, and, conveniently, theolvent for the phosgene can be an ether, or can include an ether.Suitable ethers are cyclic and aliphatic others. For example, the ethercan be tetrahydrofuran, dimethyl ether, diethyl ether, di-isopropylether, or dibutyl ether. The ether increases the yield of thechloroformate product. Maximum yields are obtained when the phosgenesolution to which the alcoholate solution is added contains as solvent acombination of hydrocarbon solvent arid ether.

The amounts of the alcoholate and phosgene reactants used can be thestoichiometric amounts. The use of larger amounts of the alcoholate ismerely wasteful. An excess of phosgene, however, can be used. Suitablephosgene excess is from about 3 to about 20%. The amount of solvent inwhich the phosgene i dissolved is not critical and can be varied overwide limits. As regards the amountof ether, small amounts exert anappreciable effect on the overall yields, of the order of 20% higherthan otherwise can be realized by not employing ethers. About 0.6 moleof ether per mol of phosgene gives good results. Smaller amounts can,however, be used.

The temperature for the alcoholate-phosgene reaction can be below C.,for example in the range of 70 to C., and preferably is 40 to 50 C.While the temperatures outside the mentioned range can be used, thiswill usually be at the expense of significantly reduced effectivenessfor the process. The time for the reaction can be 112 hours, and ispreferably 1-2 hours, and the reaction mixture is preferably agitatedduring the reaction. Atmospheric pressure can be used.

The final step, wherein the cbloroformate is reacted with ammonia i atype reaction known heretofore for production of carbamates fromchloroformates. It can be carried out by introducing ammonia gas orliquid into the solvent-chloroformate solution resulting from theprevious step. The temperature can be 50 to 0 C., and is preferably toC. Temperatures outside the ranges mentioned can be used but at theexpense of reduced effectiveness for the process. Stirring is desirable.

Reaction times are commonly from 2-7 hours, and a stoichiometric amountor a slight excess of ammonia can be used.

The following examples illustrate the practice of this mvention and arenot to be construed as limitations of the invention. The temperaturesgiven are in degrees centigrade.

EXAMPLE Preparation of 3-Methyl-3-Pentan0l Carbamate (1) PREPARATION OFSODIUM SALT OF 3-METHYL-3- PENTANOL A 500 ml. round bottom flask,equipped with stirrer, thermometer, addition funnel and a condenser,which was connected to a potassium hydroxide drying tube, was flushedthoroughly with dry nitrogen. Clean sodium (11.5 g., 0.5 mole) was addedto the flask followed by addition of the toluene (50 ml.). The mixturewas heated to 102 at which temperature the stirring and rapid additionof the diethylmethylcarbinol (52.5 g., 515 mole) was started. Themixture was then stirred rapidly at reflux (107l09) for 20 hours untilthe sodium had reacted. The clear, very pale yellow solution was thencooled, under a slow stream of nitrogen to 25. An amorphous precipitatesettled out which redissolved on addition of 30 ml. of toluene. Anadditional ml. of toluene was then added and this solution was useddirectly in the following phosgene reaction.

(2) PREPARATION OF 3-METHYL3-PENTANOL To a 1 liter flask, equipped witha stirrer, thermometer, subsurface gas inlet tube and calcium sulfatedrying tube, was charged 350 ml. of anhydrous ether. The ether wascooled to 30 by a Dry Ice-methanol bath and phosgene gas was passed intothe ether until 51 grams (0.515 mole) were dissolved. The gas inlet tubewas replaced by an addition fuel containing the toluene solution of thesalt of 3-methyl-3-pentanol prepared as in the preceding section of thisexample. 225 ml. of the sodium alcoholate solution was then added over aperiod of 30 minutes while maintaining the temperature at 45i2. Thethick mixture was then aged at 25:3 for 1 hour. During the addition andaging period the mixture was stirred as rapidly as possible withoutcausing excessive splattering on the upper part of the flask.

(3) PREPARATION OF 3-METHYL8-PENTANOL The addition funnel used in thepreparation of 3-methyl- 3-pentanol chloroformate in the precedingsection of this example was replaced by an above the surface gas inlettube and the calcium sulfate drying tube was replaced by a tube leadingto the bottom of a combustion tube containing 6 mm. of mercury. Ammoniagas from a tank was then passed into the flask with good agitation atthe rate of about .5 gram/min. for 1 hour. The temperature wasmaintained at 25i3 during the addition by periodic cooling with a DryIce-methanol bath. At the end of 1 hour the reaction mixture wasstrongly alkaline to alkacid paper. A total of 31 grams of ammonia wasused as determined by loss of Weight of the tank. The mixture wasstirred for 30 minutes at 25 and allowed to warm to room temperatureovernight without stirring.

To the thick slurry (volume-600 ml.) was added with stirring 25 ml. ofwater. The salts became considerably more dense and filtered rapidlyfrom the organic solvents. The cake was washed with 50 ml. of benzene.The cake was then removed from the funnel and slurried with 100 ml. ofbenzene. The slurry was filtered and cake was Washed with an additional50 ml. of benzene. The main filtrate and benzene washes were combinedand washed with 2 x 50 ml. of water. The second wash was still alkaline.The organic solution was dried over sodium sulfate, filtered andconcentrated to a thick syrup at 20 mm. and an internal temperature notexceeding 60 C. The residue crystallized on cooling and weighed 62grams. The product was dissolved in 120 ml. of Skellysolve B brandhexane and cooled overnight at 0. The carbamate was filtered and washedby displacement with 2 x 25 ml. of cold (0) Skellysolve B. The desiredcarbamate was air dried at room temperature, wt. 52.0 g., 71.8%, MP.5657. Amide N as NH =1-l.39, theory=1l.73.

In the foregoing example, instead of using metallic sodium, sodiumhydride or sodium amide can be used. Further, by the procedure of theexample instead of 3-methyl-3-pentanol carbamate, any one of thefollowing compounds can be made by substitution of the correspondingalcohol for the diethylmethylcarbinol of the example:

3-ethyl-3-pentanol carbamate 2-methyl-2-pentanol carbamate3-methyl-3-ol-pentyne-1 carbamate 3-methyl-3-ol-butyne-l carbamate Whilethe invention has been described in detail with reference to particularembodiments thereof, it is intended that all such modifications andalterations of the disclosed embodiments as are within the scope of theappended claims be secured by these Letters Patent.

What is claimed is:

1. The process for preparing chloroformate compounds having thestructural formula:

wherein R is selected from the group consisting of alkyl and alkynesubstituents, R is an alkyl group, and R is an alkyl group, R and Rhaving a total of 3 to 4 carbon atoms and R haw'ng 1 to 2 carbon atoms,which comprises contacting an alcohol of the formulao 112 \OH wherein RR and R are as above, with an alkaline reagent selected from the groupconsisting of alkali metals, alkali metal hydrides, and alkali metalamides, in the presence of an inert organic solvent at a temperaturebetween and the boiling point of said inert solvent, until the saidalcohol is substantially transformed into the corresponding alkali metalalcoholate as a solute in said inert organic solvent, gradually addingthe said alkali metal alcoholate solution to a solution of at least astoichimetrical amount of phosgene in an inert solvent and maintainingthe resultant reaction mixture below 0 C. to form said chloroformateester.

2. The process of claim 1 wherein there is included in said alcoholatephosgene reaction mixture an ether selected from the group consisting ofdi lower alkyl ether and tetrahydrofuran, the usage of said ether beingapproximately 0.6 mole per mole of phosgene.

3. The process of claim 1, wherein said alkali metal material is sodium.

4. The process of claim 1, wherein the inert organic solvent in thepresence of which the alcoholate is formed is toluene.

5. The process for preparing 3-methyl-3-pentanol chloroformate inaccordance with the process of claim 1, the alcohol starting materialbeing 3-methyl-3-pentanol.

6. The process of preparing 3-ethyl-3-pentanol chloroformate accordingto the process of claim 1 in which the starting alcohol is3-ethyl-3-pentanol.

7. The process for preparing 2-methyl-2-pentanol chloroformate accordingto the process of claim 1, wherein the starting alcohol is2-methyl-2-pentanol.

8. The process for preparing 3-methyl-3-o1-pentyne-1- chloroformateaccording to the process of claim 1, in which the starting alcohol is3-methyl-3-ol-pentyne.

9. The process of preparing 3-methyl-3-ol-butyne-1- chloroformateaccording to the process of claim 1, the starting alcohol being3-methyl-3-ol-butyne.

References Cited in the file of this patent UNITED STATES PATENTS2,337,172 Wojcik Dec. 21, 1943 2,430,017 Honk Nov. 4, 1947 2,816,910Junkmann et a1 Dec. 17, 1957 FOREIGN PATENTS 1,042,601 Germany Nov. 6,1958 OTHER REFERENCES Saunders et al.: J. Am. Chem. Soc., vol. 73, pp.3796- 3797 (1951). Wagner and Zook: Synthetic Organic Chemistry, pp.483-484 (1953).

1. THE PROCESS FOR PREPARING CHLOROFORMATE COMPOUNDS HAVING THESTRUCTURAL FORMULA: